EP0178260A2 - Process for the preparation of fluorinated pyridine derivatives - Google Patents

Process for the preparation of fluorinated pyridine derivatives Download PDF

Info

Publication number
EP0178260A2
EP0178260A2 EP85810455A EP85810455A EP0178260A2 EP 0178260 A2 EP0178260 A2 EP 0178260A2 EP 85810455 A EP85810455 A EP 85810455A EP 85810455 A EP85810455 A EP 85810455A EP 0178260 A2 EP0178260 A2 EP 0178260A2
Authority
EP
European Patent Office
Prior art keywords
chlorine
formula
bromine
temperature
mol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP85810455A
Other languages
German (de)
French (fr)
Other versions
EP0178260B1 (en
EP0178260A3 (en
Inventor
Rolf Dr. Schurter
Urs Siegrist
Hermann Dr. Rempfler
Peter Baumeister
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syngenta Participations AG
Original Assignee
Ciba Geigy AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
Priority to AT85810455T priority Critical patent/ATE52775T1/en
Publication of EP0178260A2 publication Critical patent/EP0178260A2/en
Publication of EP0178260A3 publication Critical patent/EP0178260A3/en
Application granted granted Critical
Publication of EP0178260B1 publication Critical patent/EP0178260B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals

Definitions

  • the present invention relates to a new process for the preparation of 2,3-difluoropyridines.
  • 2,3-difluoropyridines are valuable intermediates for the preparation of herbicides from the class of the pyridinyloxyphenoxyalkane carboxylic acid derivatives.
  • Such herbicidal active ingredients are described with their biological properties in the published European patent applications EP-A-83556 and EP-A-97460.
  • 2,3-difluoropyridines of the formula I. where X is halogen or trifluoromethyl by using a 3-amino-2-halogenopyridine of the formula II wherein X has the meaning given under formula I and Y represents bromine, chlorine or fluorine, by diazotization in the presence of hydrogen fluoride in a 3-fluoro-2-halopyridine of the formula III wherein X and Y have the meaning given under formula II, converted, and obtained 3-fluoro-2-halopyridines of the formula III, in which Y is bromine or chlorine, treated with a fluorinating agent.
  • halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, but in particular chlorine.
  • the process according to the invention is preferably used to prepare the compounds of the formula I in which X is chlorine or trifluoromethyl. Accordingly, preference is given to using those starting materials of the formula II or to passing through intermediates of the formula III in which X is chlorine or trifluoromethyl. To carry out the process, it is advantageous if the substituent Y in the starting materials and intermediates of the formulas II and III is chlorine or fluorine. The are therefore particularly suitable for carrying out the method according to the invention Compounds of the formula II in which X is chlorine or trifluoromethyl and Y is chlorine or fluorine. Correspondingly, the intermediate of formula III is run through, in which X is chlorine or trifluoromethyl and Y is chlorine.
  • the 2,3-difluoropyridines of the formula I are obtained directly by diazotization in the presence of hydrogen fluoride.
  • the process according to the invention is generally carried out in two successive reaction stages in such a way that in the first stage the amino function in the 3-position with a nitrite is diazotized and exchanged for fluorine, while in the second stage the chlorine or bromine atom in the 2-position is replaced by fluorine using a fluorinating agent.
  • the diazotization in the first reaction stage is advantageously carried out in the presence of an excess of hydrogen fluoride. At least one equivalent of hydrogen fluoride is required.
  • An inert solvent such as sulfolane, dimethyl sulfoxide, amides such as dimethylformamide, dimethylacetamide, dimethylpropyleneurea, or ether such as tetraethylene glycol dimethyl ether can be used.
  • the reaction temperature is generally chosen between -20 ° C and + 100 ° C, in particular between -10 ° C and + 70 ° C. It has proven to be advantageous to choose the temperature at the beginning of the reaction in the lower half of the interval and to increase it only to complete the reaction.
  • the pressure corresponds to the pressure that sets itself at the specific temperature. On the other hand, it is also advantageous to use a mixture of the required amount of hydrogen fluoride and one of the above mentioned solvents work.
  • the reaction temperature is chosen so that the diazonium fluoride is formed and nitrogen is split off at the same time. The use of these inert solvents enables the vapor pressure of the hydrogen fluoride to be reduced. Due to the associated pressure reduction, work can then be carried out at normal pressure. This reduces the business costs for the reactor. In this procedure, the reaction temperature is chosen between 0 ° C and + 70 ° C.
  • Nitrites are generally used as diazotizing agents; Sodium or potassium nitrite are generally common, but also dinitrogen trioxide, nitrous acid, nitrosyl halides or complexes of nitrosyl halides with the reactant hydrogen fluoride. Sodium nitrite or nitrous oxide are preferred.
  • the substitution of a chlorine or bromate in the 2-position of the pyridine body by fluorine is generally carried out in an inert polar aprotic solvent, such as dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidinone, dimethylacetamide, dimethylformamide, sulfolane or hexamethylphosphoric acid triamide.
  • the reaction temperatures are generally between 80 ° C and 220 ° C. Temperatures between 120 ° C and 170 ° C are preferred.
  • Potassium fluoride has proven to be particularly suitable as a fluorinating agent. It is used in at least an equimolar amount. Another measure which has the advantage of carrying out the reaction is the use of a fluorination catalyst.
  • Such catalysts are on the one hand heavy alkali metal fluorides such as cesium fluoride and on the other hand crown ethers such as 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, dicyclohexano-18-crown-6 or dicyclohexano-24- crown-8, or various substituted ammonium fluorides, such as Tetrabutylammonium fluoride or triethylbenzylammonium fluoride.
  • These catalysts can be added to the fluorinating agent individually or as mixtures. A catalyst addition of 0.001 to 0.1 mol per mol of starting material to be fluorinated is expedient.
  • the diazotization in the presence of hydrogen fluoride and the substitution of chlorine or bromine in the 2-position of the pyridine ring by fluorine can optionally be carried out successively in the same reactor without isolation of the intermediate or individually with intermediate isolation of the intermediate of formula III in different reactors.
  • the 3-nitropyridines of the formula IV used are known or can be prepared by processes known per se.
  • Examples H4 to H8 can optionally replace the reaction of stage b of example H1, example H9 that of stages b and c of example H1.
  • the reaction mixture is mixed with 150 al methylene chloride and poured into ice water.
  • the two-phase mixture is neutralized with concentrated ammonia solution.
  • the organic phase is separated off and the aqueous phase is extracted three times with methylene chloride.
  • the combined organic phases are washed with water, dried over sodium sulfate and filtered through silica gel. Separation of the solution by distillation gives 36.5 g (88% of theory) of 2,5-dichloro-3-fluoropyridine.
  • the reaction mixture is mixed with 150 ml of methylene chloride and in Poured ice water.
  • the two-phase mixture is neutralized with concentrated ammonia solution.
  • the organic phase is separated off, the aqueous phase is extracted several times with methylene chloride.
  • the combined organic phases are dried over sodium sulfate and evaporated. Separation of the sulfolane product solution by distillation gives 34.3 g (82.6% of theory) of 2,5-dichloro-3-fluoropyridine.
  • the reaction mixture is mixed with 150 ml of methylene chloride and poured into ice water.
  • the two-phase mixture is neutralized with concentrated ammonia solution.
  • the organic phase is separated off, the aqueous phase is extracted several times with methylene chloride.
  • the combined organic phases are dried over sodium sulfate and evaporated. After purification of the crude product by distillation, 37.9 g (91.4% of theory) of 2,5-dichloro-3-fluoropyridine are obtained.
  • the two-phase mixture is neutralized with concentrated ammonia solution.
  • the organic phase is separated off, the aqueous phase is extracted several times with methylene chloride.
  • the combined organic phases are dried over sodium sulfate and evaporated. After purification of the crude product by distillation, 36.4 g (87.8% of theory) of 2,5-dichloro-3-fluoropyridine are obtained.
  • the reaction mixture is mixed with 150 ml of methylene chloride and poured into ice water.
  • the two-phase mixture is neutralized with concentrated ammonia solution.
  • the organic phase is separated off, the aqueous phase is extracted several times with methylene chloride.
  • the combined organic phases are dried over sodium sulfate. After separation of the solution by distillation, 38.2 g (92.1% of theory) of 2,5-dichloro-3-fluoropyridine are obtained.
  • the reaction mixture is mixed with 150 ml of methylene chloride and poured onto ice water.
  • the two-phase mixture is neutralized with ammonia solution.
  • the organic phase is separated off and dried over sodium sulfate.
  • the solvent is distilled off and 200 ml of sulfolane, 166 g (2.879 mol) of potassium fluoride and 2 g of tetrabutylammonium bromide are added to the sulfolane / product mixture.
  • This reaction mixture is stirred at 179 ° C. for 7 hours.
  • the product is then distilled off directly from the sulfolane solution. After purification of the crude product by distillation, 5-chloro-2,3-difluoropyridine, b.p. 137-139 ° C. is obtained.

Abstract

In accordance with a novel process, 2,3-difluoropyridines of formula I <IMAGE> (I) wherein X is halogen or trifluoromethyl, are prepared by diazotising a 3-amino-2-halopyridine of formula II <IMAGE> (II) wherein X is as defined for formula I and Y is bromine, chlorine or fluorine, in the presence of hydrogen fluroide, to give a 3-fluoro-2-halopyridine of formula III <IMAGE> (III) wherein X and Y are as defined for formula II, and treating resultant 3-fluoro-2-halopyridines of formula III, wherein Y is bromine or chlorine, with a fluorinating agent. The 2,3-difluoropyridines prepared by the novel process are valuable intermediates for the preparation of 2-[4-(3-fluoropyridin-2-yloxy)-phenoxy]propionic acid derivatives which are known as herbicides.

Description

Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung von 2,3-Difluorpyridinen.The present invention relates to a new process for the preparation of 2,3-difluoropyridines.

2,3-Difluorpyridine sind wertvolle Zwischenprodukte für die Herstellung von Herbiziden aus der Klasse der Pyridinyloxyphenoxyalkancarbonsäure-Derivate. Derartige herbizide Wirkstoffe sind mit ihren biologischen Eigenschaften in den publizierten Europäischen Patentanmeldungen EP-A-83556 und EP-A-97460 beschrieben.2,3-difluoropyridines are valuable intermediates for the preparation of herbicides from the class of the pyridinyloxyphenoxyalkane carboxylic acid derivatives. Such herbicidal active ingredients are described with their biological properties in the published European patent applications EP-A-83556 and EP-A-97460.

Die in den publizierten Europäischen Patentanmeldungen EP-A-97460 und EP-A-104715 beschriebenen Verfahren zur Herstellung von 2,3-Difluorpyridinen erweisen sich für den grosstechnischen Einsatz als wenig geeignet, weil einerseits teuere Chemikalien wie Cäsiumfluorid mindestens in stöchiometrischen Mengen benötigt werden, aber andererseits gewünschte Produkte nur in unbefriedigenden Ausbeuten erhalten werden.The processes for the preparation of 2,3-difluoropyridines described in the published European patent applications EP-A-97460 and EP-A-104715 prove to be unsuitable for large-scale use because, on the one hand, expensive chemicals such as cesium fluoride are required at least in stoichiometric amounts, but on the other hand, desired products can only be obtained in unsatisfactory yields.

Es besteht somit ein Bedürfnis nach einem einfachen Verfahren zur Herstellung der 2,3-Difluorpyridin-Zwischenprodukte, das es ermöglicht, diese Produkte unter Einsatz billigerer Reagenzien in höheren Ausbeuten herzustellen.There is therefore a need for a simple process for the preparation of the 2,3-difluoropyridine intermediates which enables these products to be prepared in higher yields using cheaper reagents.

Ueberraschenderweise wurde nun ein neues Verfahren zur Herstellung dieser wertvollen Zwischenprodukte gefunden, das dieses Bedürfnis weitgehend befriedigt.Surprisingly, a new process for the production of these valuable intermediates has now been found which largely satisfies this need.

Gemäss vorliegender Erfindung wird daher vorgeschlagen, 2,3-Difluorpyridine der Formel I

Figure imgb0001
worin X für Halogen oder Trifluormethyl steht, herzustellen, indem man ein 3-Amino-2-halogenpyridin der Formel II
Figure imgb0002
worin X die unter Formel I gegebene Bedeutung hat und Y für Brom, Chlor oder Fluor steht, durch Diazotieren in Gegenwart von Fluorwasserstoff in ein 3-Fluor-2-halogenpyridin der Formel III
Figure imgb0003
worin X und Y die unter Formel II gegebene Bedeutung haben, überführt, und erhaltene 3-Fluor-2-halogenpyridine der Formel III, in welchen Y Brom oder Chlor bedeutet, mit einem Fluorierungsmittel behandelt.According to the present invention, it is therefore proposed to use 2,3-difluoropyridines of the formula I.
Figure imgb0001
 where X is halogen or trifluoromethyl, by using a 3-amino-2-halogenopyridine of the formula II
Figure imgb0002
 wherein X has the meaning given under formula I and Y represents bromine, chlorine or fluorine, by diazotization in the presence of hydrogen fluoride in a 3-fluoro-2-halopyridine of the formula III
Figure imgb0003
 wherein X and Y have the meaning given under formula II, converted, and obtained 3-fluoro-2-halopyridines of the formula III, in which Y is bromine or chlorine, treated with a fluorinating agent.

In den Formeldefinitionen steht Halogen für Fluor, Chlor, Brom oder Jod, vorzugsweise für Fluor, Chlor oder Brom, jedoch insbesondere für Chlor.In the formula definitions, halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, but in particular chlorine.

Vorzugsweise wird das erfindungsgemässe Verfahren eingesetzt, um die Verbindungen der Formel I herzustellen, wcrin X für Chlor oder Trifluormethyl steht. Entsprechend werden bevorzugt solche Ausgangsmaterialien der Formel II verwendet, bzw. Zwischenprodukte der Formel III durchlaufen, in denen X für Chlor oder Trifluormethyl steht. Für die Durchführung des Verfahrens ist es von Vorteil, wenn der Substituent Y in den Ausgangs- und Zwischenprodukten der Formeln II und III für Chlor oder Fluor steht. Insbesondere eignen sich deshalb für die Durchführung des erfindungsgemässen Verfahrens die Verbindungen der Formel II, worin X Chlor oder Trifluormethyl und Y Chlor oder Fluor bedeuten. Entsprechend wird das Zwischenprodukt der Formel III durchlaufen, worin X Chlor oder Trifluormethyl und Y Chlor bedeuten.The process according to the invention is preferably used to prepare the compounds of the formula I in which X is chlorine or trifluoromethyl. Accordingly, preference is given to using those starting materials of the formula II or to passing through intermediates of the formula III in which X is chlorine or trifluoromethyl. To carry out the process, it is advantageous if the substituent Y in the starting materials and intermediates of the formulas II and III is chlorine or fluorine. The are therefore particularly suitable for carrying out the method according to the invention Compounds of the formula II in which X is chlorine or trifluoromethyl and Y is chlorine or fluorine. Correspondingly, the intermediate of formula III is run through, in which X is chlorine or trifluoromethyl and Y is chlorine.

Bei Verwendung von 3-Amino-2-halogenpyridinen der Formel II, in welchen Y Fluor bedeutet, werden die 2,3-Difluorpyridine der Formel I durch Diazotieren in Gegenwart von Fluorwasserstoff direkt erhalten. Bei Verwendung von 3-Amino-2-halogenpyridinen der Formel II, in welchen Y Chlor oder Brom bedeutet, wird das erfindungsgemässe Verfahren im allgemeinen in zwei aufeinanderfolgenden Reaktionsstufen in der Weise durchgeführt, dass in der ersten Stufe die Aminofunktion in der 3-Stellung mit einem Nitrit diazotiert und gegen Fluor ausgetauscht wird, während in der zweiten Stufe das Chlor- oder Bromatom in der 2-Stellung mittels eines Fluorierungsmittels durch Fluor ersetzt wird.When using 3-amino-2-halopyridines of the formula II in which Y is fluorine, the 2,3-difluoropyridines of the formula I are obtained directly by diazotization in the presence of hydrogen fluoride. When using 3-amino-2-halopyridines of the formula II, in which Y is chlorine or bromine, the process according to the invention is generally carried out in two successive reaction stages in such a way that in the first stage the amino function in the 3-position with a nitrite is diazotized and exchanged for fluorine, while in the second stage the chlorine or bromine atom in the 2-position is replaced by fluorine using a fluorinating agent.

Die Diazotierung auf der ersten Reaktionsstufe führt man mit Vorteil in Gegenwart eines Ueberschusses von Fluorwasserstoff aus. Mindestens erforderlich ist ein Aequivalent Fluorwasserstoff. Dabei kann ein inertes Lösungsmittel verwendet werden, wie z.B. Sulfolan, Dimethylsulfoxid, Amide, wie Dimethylformamid, Dimethylacetamid, Dimethylpropylenharnstoff, oder Aether wie Tetraäthylenglykoldimethyläther. Besonders vorteilhaft ist es jedoch, die Reaktion in flüssigem Fluorwasserstoff durchzuführen. Wegen des niedrigen Siedepunktes von Fluorwasserstoff ist es von Vorteil, die Reaktion in einem Autoklaven ablaufen zu lassen, um gewünschtenfalls die Reaktionstemperatur über den Siedepunkt von Fluorwasserstoff hinaus anheben zu können. Die Reaktionstemperatur wird im allgemeinen zwischen -20°C und +100°C, insbesondere zwischen -10°C und + 70°C, gewählt. Als günstig hat es sich erwiesen, die Temperatur zu Beginn der Reaktion in der unteren Hälfte des Intervalls zu wählen und sie erst zur Vervollständigung der Reaktion zu erhöhen. Der Druck entspricht dabei dem sich selbst bei der bestimmten Temperatur einstellenden Druck. Andererseits kann man mit Vorteil auch in einem Gemisch der nötigen Menge Fluorwasserstoff und einem der oben genannten Lösungsmittel arbeiten. Dabei wird die Reaktionstemperatur so gewählt, dass sich das Diazoniumfluorid bildet und gleichzeitig Stickstoff abspaltet. Der Einsatz dieser inerten Lösungsmittel ermöglicht eine Senkung des Dampfdrucks des Fluorwasserstoffs. Durch die damit verbundene Druckminderung kann dann bei Normaldruck gearbeitet werden. Damit werden die betriebswirtschaftlichen Kosten für den Reaktor gesenkt. Bei dieser Verfahrensweise wird die Reaktionstemperatur zwischen 0°C und +70°C gewählt.The diazotization in the first reaction stage is advantageously carried out in the presence of an excess of hydrogen fluoride. At least one equivalent of hydrogen fluoride is required. An inert solvent such as sulfolane, dimethyl sulfoxide, amides such as dimethylformamide, dimethylacetamide, dimethylpropyleneurea, or ether such as tetraethylene glycol dimethyl ether can be used. However, it is particularly advantageous to carry out the reaction in liquid hydrogen fluoride. Because of the low boiling point of hydrogen fluoride, it is advantageous to allow the reaction to take place in an autoclave in order, if desired, to be able to raise the reaction temperature above the boiling point of hydrogen fluoride. The reaction temperature is generally chosen between -20 ° C and + 100 ° C, in particular between -10 ° C and + 70 ° C. It has proven to be advantageous to choose the temperature at the beginning of the reaction in the lower half of the interval and to increase it only to complete the reaction. The pressure corresponds to the pressure that sets itself at the specific temperature. On the other hand, it is also advantageous to use a mixture of the required amount of hydrogen fluoride and one of the above mentioned solvents work. The reaction temperature is chosen so that the diazonium fluoride is formed and nitrogen is split off at the same time. The use of these inert solvents enables the vapor pressure of the hydrogen fluoride to be reduced. Due to the associated pressure reduction, work can then be carried out at normal pressure. This reduces the business costs for the reactor. In this procedure, the reaction temperature is chosen between 0 ° C and + 70 ° C.

Als Diazotierungsmittel werden im allgemeinen Nitrite verwendet; allgemein üblich sind Natrium- oder Kaliumnitrit, aber auch Distickstofftrioxid, salpetrige Säure, Nitrosylhalogenide oder Komplexe von Nitrosylhalogeniden mit dem Reaktionspartner Fluorwasserstoff. Bevorzugt sind Natriumnitrit oder Distickstofftrioxid.Nitrites are generally used as diazotizing agents; Sodium or potassium nitrite are generally common, but also dinitrogen trioxide, nitrous acid, nitrosyl halides or complexes of nitrosyl halides with the reactant hydrogen fluoride. Sodium nitrite or nitrous oxide are preferred.

Die Substitution eines Chlor- oder Bromatoss in der 2-Stellung des Pyridinkörpers durch Fluor wird im allgemeinen in einem inerten polaren aprotischen Lösungsmittel, wie Dimethylsulfoxid, Dimethylsulfon, N-Methylpyrrolidinon, Dimethylacetamid, Dimethylformamid, Sulfolan oder Hexamethylphosphorsäuretriamid, durchgeführt. Die Reaktionstemperaturen liegen allgemein zwischen 80°C und 220°C. Bevorzugt sind Temperaturen zwischen 120°C und 170°C. Als Fluorierungsmittel hat sich Kaliumfluorid als besonders geeignet erwiesen. Man setzt es in mindestens äquimolarer Menge ein. Eine weitere sich zum Vorteil der Reaktionsführung auswirkende Massnahme ist der Einsatz eines Fluorierungskatalysators. Solche Katalysatoren sind einerseits schwere Alkalimetallfluoride wie Cäsiumfluorid und andererseits Kronenäther wie 12-Crown-4, 15-Crown-5, 18-Crown-6, Dibenzo-18-crown-6, Dicyclohexano-18-crown-6 oder Dicyclohexano-24- crown-8, oder auch verschiedene substituierte Ammoniumfluoride, wie z.B. Tetrabutylammoniumfluorid oder Triäthylbenzylammoniumfluorid. Diese Katalysatoren können einzeln oder auch als Gemische dem Fluorierungsmittel zugesetzt werden. Zweckmässig ist ein Katalysatorzusatz von 0,001 bis 0,1 Mol pro Mol zu fluorierendes Ausgangsmaterial.The substitution of a chlorine or bromate in the 2-position of the pyridine body by fluorine is generally carried out in an inert polar aprotic solvent, such as dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidinone, dimethylacetamide, dimethylformamide, sulfolane or hexamethylphosphoric acid triamide. The reaction temperatures are generally between 80 ° C and 220 ° C. Temperatures between 120 ° C and 170 ° C are preferred. Potassium fluoride has proven to be particularly suitable as a fluorinating agent. It is used in at least an equimolar amount. Another measure which has the advantage of carrying out the reaction is the use of a fluorination catalyst. Such catalysts are on the one hand heavy alkali metal fluorides such as cesium fluoride and on the other hand crown ethers such as 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, dicyclohexano-18-crown-6 or dicyclohexano-24- crown-8, or various substituted ammonium fluorides, such as Tetrabutylammonium fluoride or triethylbenzylammonium fluoride. These catalysts can be added to the fluorinating agent individually or as mixtures. A catalyst addition of 0.001 to 0.1 mol per mol of starting material to be fluorinated is expedient.

Die Diazotierung in Gegenwart von Fluorwasserstoff und die Substitution von Chlor oder Brom in 2-Stellung des Pyridinringes durch Fluor können wahlweise nacheinander im gleichen Reaktor ohne Isolierung des Zwischenproduktes oder einzeln unter zwischenzeitlicher Isolierung des Zwischenproduktes der Formel III in verschiedenen Reaktoren durchgeführt werden.The diazotization in the presence of hydrogen fluoride and the substitution of chlorine or bromine in the 2-position of the pyridine ring by fluorine can optionally be carried out successively in the same reactor without isolation of the intermediate or individually with intermediate isolation of the intermediate of formula III in different reactors.

Die Ausgangsmaterialien und Zwischenprodukte der Formeln II und III sind bekannt für den Fall, dass X Trifluormethyl bedeutet.The starting materials and intermediates of formulas II and III are known for the case where X means trifluoromethyl.

Die Verbindungen der Formeln II und III, worin X für Halogen steht, sind neu und wurden speziell im Zusammenhang mit dem erfindungsgemässen Verfahren entwickelt und hergestellt. Diese neuen Verbindungen, das heisst Verbindungen der Formel IIa

Figure imgb0004
worin X für Halogen und Y für Brom, Chlor oder Fluor stehen, und Verbindungen der Formel IIIa
Figure imgb0005
worin X für Halogen und Y für Brom oder Chlor stehen, bilden daher einen Bestandteil der vorliegenden Erfindung.The compounds of the formulas II and III, in which X represents halogen, are new and were developed and produced specifically in connection with the process according to the invention. These new compounds, that is to say compounds of the formula IIa
Figure imgb0004
 where X is halogen and Y is bromine, chlorine or fluorine, and compounds of the formula IIIa
Figure imgb0005
 where X is halogen and Y is bromine or chlorine, therefore form part of the present invention.

Die Verbindungen der Formel II werden aus den entsprechenden 3-Nitropyridin-Derivaten der Formel IV

Figure imgb0006
worin X und Y die unter Formel II gegebene Bedeutung haben, durch katalytische Reduktion mit Wasserstoff hergestellt. Uebliche dem Fachmann geläufige angewendete Reaktionsbedingungen dafür sind:

  • - Wasserstoffdrucke zwischen 1 und 20 bar, vorzugsweise 1 bis 5 bar;
  • - Reaktionstemperaturen zwischen -20°C und + 50°C, vorzugsweise zwischen 0°C und 30°C;
  • - inertes Lösungsmittel aus der Reihe: Aether, Ester, Alkohole oder Kohlenwasserstoff; vorzugsweise: Tetrahydrofuran, Dioxan, Diäthyl- äther, Aethylacetat, Methanol, Aethanol, Pentan, Cyclohexan oder Benzol; und
  • - Hydrierungskatalysatoren aus der 8. Nebengruppe des Periodischen Systems der Elemente: Nickel, Palladium oder Platin in handelsüblicher Form wie zum Beispiel als Raney-Nickel, Palladium auf Kohle, Platinoxid oder Platinmoor.
The compounds of formula II are made from the corresponding 3-nitropyridine derivatives of formula IV
Figure imgb0006
 where X and Y have the meaning given under formula II, prepared by catalytic reduction with hydrogen. Typical reaction conditions for this which are familiar to the person skilled in the art are:
  • - Hydrogen pressures between 1 and 20 bar, preferably 1 to 5 bar;
  • - Reaction temperatures between -20 ° C and + 50 ° C, preferably between 0 ° C and 30 ° C;
  • - inert solvent from the series: ethers, esters, alcohols or hydrocarbons; preferably: tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, methanol, ethanol, pentane, cyclohexane or benzene; and
  • - Hydrogenation catalysts from subgroup 8 of the Periodic Table of the Elements: nickel, palladium or platinum in commercially available form such as Raney nickel, palladium on carbon, platinum oxide or platinum moor.

Die eingesetzten 3-Nitropyridine der Formel IV sind bekannt oder können nach an sich bekannten Verfahren hergestellt werden.The 3-nitropyridines of the formula IV used are known or can be prepared by processes known per se.

Aus den erfindungsgemäss hergestellten 2,3-Difluorpyridinen erhält man die wertvollen Herbizide aus der Klasse der 2-[4-(3-Fluorpyri- din-2-yloxy)-phenoxy]-propionsäure-Abkömmlinge beispielsweise nach den Reaktionen, wie sie im nachfolgenden Schema 1 zusammengefasst sind:

Figure imgb0007
Hal steht für Halogen, vorzugsweise Chlor oder Brom, R für einen beliebigen organischen Rest.The valuable herbicides from the class of 2- [4- (3-fluoropyridin-2-yloxy) phenoxy] propionic acid derivatives are obtained from the 2,3-difluoropyridines prepared according to the invention, for example after the reactions as described below Scheme 1 summarizes:
Figure imgb0007
 Hal represents halogen, preferably chlorine or bromine, R represents any organic radical.

Die anschliessenden Beispiele dienen der näheren Illustration der vorliegenden Erfindung. Die Beispiele H4 bis H8 können wahlweise die Reaktion der Stufe b des Beispiels H1, das Beispiel H9 die der Stufen b und c des Beispiels H1 ersetzen.The following examples serve to illustrate the present invention in more detail. Examples H4 to H8 can optionally replace the reaction of stage b of example H1, example H9 that of stages b and c of example H1.

Herstellungsbeispiele:Manufacturing examples: Beispiel H1: 5-Chlor-2,3-difluorpyridinExample H1: 5-chloro-2,3-difluoropyridine

  • a) 3-Amino-2,5-dichlorpyridin
    26,0 g Raney-Nickel-Katalysator werden mit Aethanol gewaschen und einer Lösung von 129,2 g (0,69 mol) 2,5-Dichlor-3-nitropyridin in 1300 ml Dioxan zugesetzt. Diese Mischung wird unter Normaldruck bei einer Temperatur zwischen 20° und 35°C mit Wasserstoff hydriert. Nach Umsetzung von 20 % der erforderlichen Wasserstoffmenge setzt man der Reaktionsmischung weitere 30,0 g Raney-Nickel-Katalysator zu. Nach einer Hydrierdauer von 22 Stunden wird der Katalysator abgetrennt, das Lösungsmittel abgedampft und der Rückstand aus Aethylacetat/Hexan kristallisiert. Man erhält so 84,9 g (78 % d.Th.) 3-Amino-2,5-dichlorpyridin, Smp. 129-132°C.    a) 3-Amino-2,5-dichloropyridine
    26.0 g of Raney nickel catalyst are washed with ethanol and a solution of 129.2 g (0.69 mol) of 2,5-dichloro-3-nitropyridine in 1300 ml of dioxane is added. This mixture is hydrogenated under normal pressure at a temperature between 20 ° and 35 ° C with hydrogen. After 20% of the required amount of hydrogen has been converted, a further 30.0 g of Raney nickel catalyst are added to the reaction mixture. After a hydrogenation period of 22 hours, the catalyst is separated off, the solvent is evaporated off and the residue is crystallized from ethyl acetate / hexane. This gives 84.9 g (78% of theory) of 3-amino-2,5-dichloropyridine, mp. 129-132 ° C.
  • b) 2,5-Dichlor-3-fluorpyridin
    In einem Monel-Autoklaven werden 450 ml (22,5 mol) Fluorwasserstoff vorgelegt und bei einer Temperatur zwischen -5°C und -1°C mit 163 g (1,0 mol) 3-Amino-2,5-dichlorpyridin versetzt. Innerhalb von 1,5 Stunden werden in diese Lösung 82,8 g (1,2 mol) Natriumnitrit eingetragen. Nachdem die Reaktionsmischung bei der gleichen Temperatur für 1,5 Stunden gerührt worden ist, wird die Temperatur stufenweise auf +60°C erhöht. Wenn keine Gasentwicklung mehr stattfindet, wird der Fluorwasserstoff abgedampft, der Rückstand in Methylenchlorid aufgenommen und in Eiswasser eingegossen. Das zweiphasige Gemisch wird mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt, die wässrige dreimal mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden mit Wasser gewaschen, über Magnesiumsulfat getrocknet, mit Aktivkohle behandelt, durch Kieselgel filtriert und eingedampft. Man erhält so 141,5 g (85 % d.Th.) 2,5-Dichlor-3-fluorpyridin, Smp. 38-39°C.    b) 2,5-dichloro-3-fluoropyridine
    450 ml (22.5 mol) of hydrogen fluoride are placed in a Monel autoclave and 163 g (1.0 mol) of 3-amino-2,5-dichloropyridine are added at a temperature between -5 ° C. and -1 ° C. 82.8 g (1.2 mol) of sodium nitrite are introduced into this solution within 1.5 hours. After the reaction mixture has been stirred at the same temperature for 1.5 hours, the temperature is gradually increased to + 60 ° C. When gas evolution ceases, the hydrogen fluoride is evaporated off, the residue is taken up in methylene chloride and poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution lized. The organic phase is separated off and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed with water, dried over magnesium sulfate, treated with activated carbon, filtered through silica gel and evaporated. This gives 141.5 g (85% of theory) of 2,5-dichloro-3-fluoropyridine, mp. 38-39 ° C.
  • c) 64,6 g (1,11 mol) Kaliumfluorid und 11,25 g (0,074 mol) Cäsiumfluorid werden in 240 ml Sulfolan suspendiert und auf 140°C erhitzt. Durch Druckverminderung destilliert man 50 ml Sulfolan ab und setzt anschliessend der Suspension 61,4 g (0,37 mol) 2,5-Dichlor-3-fluor- pyridin und 1,45 g (0,0055 mol) 18-Crown-6 in 20 ml Sulfolan zu. Dieses Reaktionsgemisch wird für 35 Stunden bei einer Temperatur von 140°C gerührt und dann in Eiswasser aufgenommen. Aus dem wasserhaltigen Gemisch wird das Produkt entweder durch Extraktion mit Aether oder durch Wasserdampfdestillation isoliert. Man erhält so 48,7 g (88% d.Th.) 5-Chlor-2,3-difluorpyridin, Sdp. 65-66°C bei 133 mbar.c) 64.6 g (1.11 mol) of potassium fluoride and 11.25 g (0.074 mol) of cesium fluoride are suspended in 240 ml of sulfolane and heated to 140 ° C. By reducing the pressure, 50 ml of sulfolane are distilled off and 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine and 1.45 g (0.0055 mol) of 18-crown-6 are then added to the suspension in 20 ml of sulfolane. This reaction mixture is stirred for 35 hours at a temperature of 140 ° C and then taken up in ice water. The product is isolated from the water-containing mixture either by extraction with ether or by steam distillation. This gives 48.7 g (88% of theory) of 5-chloro-2,3-difluoropyridine, b.p. 65-66 ° C at 133 mbar.
Beispiel H2: 2-[4-(5-Chlor-3-fluorpyridin-2-yl-oxy)-phenoxy]-propionsäuremethylesterExample H2: methyl 2- [4- (5-chloro-3-fluoropyridin-2-yl-oxy) phenoxy] propionate

Zu einer Mischung von 21,6 g (0,11 mol) 2-(4-Hydroxyphenoxy)-prop- ionsäuremethylester, 15,2 g (0,11 mcl) Kallumcarbonat, 1,45 g (0,0055 mol) 18-Crown-6 und 100 ml Acetonitril lässt man eine Lösung von 14,95 g (0,10 mol) 5-Chlor-2,3-difluorpyridin in 30 ml Acetonitril zutropfen und erhitzt das Reaktionsgemisch für 40 Stunden auf eine Temperatur zwischen 50°C und 60°C. Durch Aufnahmen der Mischung in Eiswasser, Abtrennen der organischen Phase, dreimalige Extraktion der wässrigen Phase mit Aethylacetat, Trockner und Eindampfen der vereinigten organischen Phasen erhält man einen öligen Rückstand, der durch Lösen in Hexan/Aethylacetat-Gemisch und Filtration über Kieselgel gereinigt wird. Durch Verdampfen des Lösungsmittels erhält man aus dem Filtrat 20,4 g (63% d.Th.) 2-[4-(5-Chlor-3-fluorpyridin-2-yloxy)-phenoxy]-propionsäuremethyl-ester, Smp. 58-59°C.To a mixture of 21.6 g (0.11 mol) methyl 2- (4-hydroxyphenoxy) propionate, 15.2 g (0.11 mcl) callum carbonate, 1.45 g (0.0055 mol) 18- Crown-6 and 100 ml of acetonitrile are added dropwise to a solution of 14.95 g (0.10 mol) of 5-chloro-2,3-difluoropyridine in 30 ml of acetonitrile and the reaction mixture is heated to a temperature between 50 ° C. for 40 hours and 60 ° C. By taking up the mixture in ice water, separating the organic phase, extracting the aqueous phase three times with ethyl acetate, drying and evaporating the combined organic phases, an oily residue is obtained which is purified by dissolving in a hexane / ethyl acetate mixture and filtering through silica gel. Evaporation of the solvent gives 20.4 g (63% of theory) of methyl 2- [4- (5-chloro-3-fluoropyridin-2-yloxy) phenoxy] propionate, mp 58, from the filtrate -59 ° C.

Beispiel H3: 2,3-Difluor-5-trifluormethylpyridinExample H3: 2,3-difluoro-5-trifluoromethylpyridine

  • a) 3-Amino-2-chlor-5-trifluormethylpyridin
    12,3 g (0,0543 mol) 2-Chlor-3-nitro-5-trifluormethylpyridin werden in 250 ml Aethanol gelöst, 2,4 g Raney-Nickel-Katalysator zugesetzt und unter Normaldruck bei einer Temperatur zwischen 20° und 25°C mit Wasserstoff hydriert. Nach einer Hydrierdauer von 28 Stunden wird der Katalysator abgetrennt, das Lösungsmittel abdestilliert und der Rückstand aus Aethylacetat/Hexan kristallisiert. Man erhält so 9,0 g (84 % d.Th.) 3-Amino-2-chlor-5-trifluormethylpyridin, Smp. 94-95°C.    a) 3-Amino-2-chloro-5-trifluoromethylpyridine
    12.3 g (0.0543 mol) of 2-chloro-3-nitro-5-trifluoromethylpyridine are dissolved in 250 ml of ethanol, 2.4 g of Raney nickel catalyst are added and under normal pressure at a temperature between 20 ° and 25 ° C hydrogenated with hydrogen. After a hydrogenation period of 28 hours, the catalyst is separated off, the solvent is distilled off and the residue is crystallized from ethyl acetate / hexane. This gives 9.0 g (84% of theory) of 3-amino-2-chloro-5-trifluoromethylpyridine, mp. 94-95 ° C.
  • b) 2-Chlor-3-fluor-5-trifluormethylpyridin
    In einem Monel-Autoklaven werden 120 g (6,0 mol) Fluorwasserstoff vorgelegt und bei einer Temperatur zwischen -5°C und 0°C mit 27,0 g (0,137 mol) 3-Amino-2-chlor-5-trifluormethylpyridin versetzt. Innerhalb von einer Stunde werden in diese Lösung 10,35 g (0,15 mol) Natriumnitrit eingetragen. Nachdem die Reaktionsmischung bei der gleichen Temperatur während 2 Stunden gerührt worden ist, wird die Temperatur stufenweise auf 50°C erhöht. Wenn keine Stickstoffentwicklung mehr stattfindet, wird der Fluorwasserstoff abgedampft, der Rückstand in Methylenchlorid aufgenommen und in Eiswasser eingegossen. Das zweiphasige Gemisch wird unter guter Kühlung mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt und die wässerige dreimal mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden mit Wasser gewaschen, über Magnesiumsulfat getrocknet und durch etwas Kieselgel filtriert. Nach dem Abdestillieren des Lösungsmittels wird das erhaltene Produkt destilliert, Sdp. 113°C (975 mbar).    b) 2-chloro-3-fluoro-5-trifluoromethylpyridine
    120 g (6.0 mol) of hydrogen fluoride are placed in a Monel autoclave, and 27.0 g (0.137 mol) of 3-amino-2-chloro-5-trifluoromethylpyridine are added at a temperature between -5 ° C. and 0 ° C. . 10.35 g (0.15 mol) of sodium nitrite are introduced into this solution within one hour. After the reaction mixture has been stirred at the same temperature for 2 hours, the temperature is gradually increased to 50 ° C. When nitrogen evolution ceases, the hydrogen fluoride is evaporated off, the residue is taken up in methylene chloride and poured into ice water. The two-phase mixture is neutralized with good cooling with concentrated ammonia solution. The organic phase is separated off and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed with water, dried over magnesium sulfate and filtered through a little silica gel. After the solvent has been distilled off, the product obtained is distilled, bp 113 ° C. (975 mbar).
  • c) 47,7 g (0,82 mol) Kaliumfluorid und 10,0 g (0,065 mol) Cäsiumfluorid werden in 300 ml Sulfolan suspendiert und auf 140°C erhitzt. Durch Druckverminderung destilliert man 60 ml Sulfolan ab und setzt anschliessend der Suspension 65,6 g (0,329 mol) 2-Chlor-3-fluor-5-trifluormethylpyridin und 1,3 g (0,004 mol) 18-Crown-6 zu. Das Reaktionsgemisch wird für 48 Stunden bei einer Temperatur von 140°C gerührt und anschliessend unter Einleitung von Wasserdampf destilliert. Das Oel wird abgetrennt und die wässerige phase zweimal mit wenig Aether extrahiert. Die organischen Phasen werden bereinigt, mit etwas Magnesiumsulfat getrocknet und filtriert. Durch Destillation erhält man 54,8 g (91 % d.Th.) 2,3-Difluor-5-trifluormethyl- pyridin, Sdp. 100-102°C (980 mbar).c) 47.7 g (0.82 mol) of potassium fluoride and 10.0 g (0.065 mol) of cesium fluoride are suspended in 300 ml of sulfolane and heated to 140 ° C. By reducing the pressure, 60 ml of sulfolane are distilled off and then 65.6 g (0.329 mol) of 2-chloro-3-fluoro-5-trifluoromethylpyridine and 1.3 g (0.004 mol) of 18-crown-6 are added to the suspension. The reaction mixture is stirred for 48 hours at a temperature of 140 ° C and then distilled while introducing steam liert. The oil is separated off and the aqueous phase is extracted twice with a little ether. The organic phases are cleaned, dried with a little magnesium sulfate and filtered. Distillation gives 54.8 g (91% of theory) of 2,3-difluoro-5-trifluoromethyl-pyridine, b.p. 100-102 ° C (980 mbar).
Beispiel H4: 2,5-Dichlor-3-fluorpyridinExample H4: 2,5-dichloro-3-fluoropyridine

In einem 500 ml Reaktor aus Polytetrafluoräthylen, der mit Rührwerk, Thermometer und Rückflusskühler ausgerüstet ist, werden 120 g Fluorwasserstoff vorgelegt. Bei einer Temperatur zwischen 0°C und +10°C werden 40,7 g (0,25 mol) 3-Amino-2,5-dichlorpyridin gelöst in 60 ml Dimethylsulfoxid zugetropft. Bei einer Temperatur von +40°C werden in diese Lösung 20,7 g (0,3 mol) Natriumnitrit eingetragen. Der entstehende Stickstoff wird über den Rückflusekühler aus dem Reaktor entfernt. Nach 4 Stunden bei +40°C ist die Gasentwicklung beendet. Das Reaktionsgemisch wird mit 150 al Methylenchlorid versetzt und in Eiswasser eingegossen. Das zweiphasige Gemisch wird mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt, die wässrige Phase dreimal mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden mit Wasser gewaschen, über Natriumsulfat getrocknet und durch Kieselgel filtriert. Durch destillative Trennung der Lösung erhält man 36,5 g (88 % d.Th) 2,5-Dichlor-3-fluorpyridin.120 g of hydrogen fluoride are placed in a 500 ml reactor made of polytetrafluoroethylene, which is equipped with a stirrer, thermometer and reflux condenser. 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine dissolved in 60 ml of dimethyl sulfoxide are added dropwise at a temperature between 0 ° C. and + 10 ° C. At a temperature of + 40 ° C, 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution. The nitrogen produced is removed from the reactor via the reflux condenser. After 4 hours at + 40 ° C the gas evolution has ended. The reaction mixture is mixed with 150 al methylene chloride and poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated off and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and filtered through silica gel. Separation of the solution by distillation gives 36.5 g (88% of theory) of 2,5-dichloro-3-fluoropyridine.

Beispiel H5: 2,5-Dichlor-3-fluorpyridinExample H5: 2,5-dichloro-3-fluoropyridine

In einem 500 ml Reaktor aus Polytetrafluoräthylen, der mit Rührwerk, Thermometer und Rückflusskühler ausgerüstet ist, werden 60 g Fluorwasserstoff vorgelegt. Bei einer Temperatur zwishen 0°C und +10°C werden 40,7 g (0,25 mol) 3-Amino-2,5-dichlorpyridin gelöst in 100 ml Sulfolan zugetropft. Bei einer Temperatur von + 50°C werden in diese Lösung 20,7 g (0,3 mol) Natriumnitrit eingetragen. Der entstehende Stickstoff wird über den Rückflusskühler aus dem Reaktor entfernt. Nach 2 Stunden bei + 50°C ist die Gasentwicklung beendet. Das Reaktionsgemisch wird mit 150 ml Methylenhlorid versetzt und in Eiswasser eingegossen. Das zweiphasige Gemisch wird mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt, die wässrige Phase mehrmals mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und eingedampft. Durch destillative Trennung der Sulfolan-Produkt-Lösung erhält man 34,3 g (82,6 % d.Th) 2,5-Dichlor-3-fluor- pyridin.60 g of hydrogen fluoride are placed in a 500 ml reactor made of polytetrafluoroethylene, which is equipped with a stirrer, thermometer and reflux condenser. At a temperature between 0 ° C and + 10 ° C, 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine dissolved in 100 ml of sulfolane are added dropwise. 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at a temperature of + 50 ° C. The nitrogen produced is removed from the reactor via the reflux condenser. After 2 hours at + 50 ° C the gas evolution has ended. The reaction mixture is mixed with 150 ml of methylene chloride and in Poured ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated off, the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. Separation of the sulfolane product solution by distillation gives 34.3 g (82.6% of theory) of 2,5-dichloro-3-fluoropyridine.

Beispiel H6: 2,5-Dichlor-3-fluorpyridinExample H6: 2,5-dichloro-3-fluoropyridine

In einem 500 ml Reaktor aus PolytetraLluoräthylen, der mit Rührwerk, Thermometer and Rückflusskühler ausgerüstet ist, werden 120 g Fluorwasserstoff vorgelegt. Bei einer Temperatur zwishen 0°C und +10°C werden 40,7 g (0,25 mol) 3-Amino-2,5-dichorpyridin gelöst in 100 ml Dimethylformamid zugetropft. Bei einer Temperatur von 55°C werden in diese Lösung 20,7 g (0,3 mol) Natriumnitrit eingetragen. Der entstehende Stick3toff wird über den Rückflusskühler aus dem Reaktor entfernt. Nach 2 Stunden bei +50°C ist die Gasentwicklng beendet. Das Reaktionsgemisch wird mit 150 ml Methylenchlorid versetzt und in Eiswasser eingegossen. Das zweiphasige Gemisch wird mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt, die wässrige Phase mehrmals mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und eingedampft. Nach destillativer Reinigung des Rohprodukts erhält man 37,9 g (91,4 % d.Th) 2,5-Dichlor-3-fluorpyridin.120 g of hydrogen fluoride are placed in a 500 ml reactor made of polytetrafluoroethylene, which is equipped with a stirrer, thermometer and reflux condenser. At a temperature between 0 ° C and + 10 ° C, 40.7 g (0.25 mol) of 3-amino-2,5-dichoropyridine dissolved in 100 ml of dimethylformamide are added dropwise. At a temperature of 55 ° C 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution. The resulting nitrogen is removed from the reactor via the reflux condenser. The gas evolution ceases after 2 hours at + 50 ° C. The reaction mixture is mixed with 150 ml of methylene chloride and poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated off, the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. After purification of the crude product by distillation, 37.9 g (91.4% of theory) of 2,5-dichloro-3-fluoropyridine are obtained.

Beispiel H7: 2,5-Dichlor-3-fluorpyridinExample H7: 2,5-dichloro-3-fluoropyridine

In einem 500 ml Reaktor aus Polytetrafluoräthylen, der mit Rührwerk, Thermometer und Rückflusskühler ausgerüstet ist, werden 120 g Fluorwasserstoff vorgelegt. Bei einer Temperatur zwischen 0°C und +10°C werden 40,7 g (0,25 mol) 3-Amino-2,5-dichlorpyridin gelöst in 100 ml Dimethylacetamid zugetropft. Bei einer Temperatur von 55°C werden in diese Lösung 20,7 (0,3 mol) Natriumnitrit eingetragen. Der entstehende Stickstoff wird über den Rückflusskühler aus dem Reaktor entfernt. Nach 2,5 Stunden bei 55°C ist die Gasentwicklung beendet. Das Reaktionsgemisch wird mit 150 ml Methylenchlorid versetzt und in Eiswasser gegossen. Das zweiphasige Gemisch wird mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt, die wässrige Phase mehrmals mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und eingedampft. Nach destillativer Reinigung des Rohprodukts erhält man 36,4 g (87,8 % d.Th.) 2,5-Dichlor-3-fluorpyridin.120 g of hydrogen fluoride are placed in a 500 ml reactor made of polytetrafluoroethylene, which is equipped with a stirrer, thermometer and reflux condenser. 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine dissolved in 100 ml of dimethylacetamide are added dropwise at a temperature between 0 ° C. and + 10 ° C. 20.7 (0.3 mol) sodium nitrite are introduced into this solution at a temperature of 55 ° C. The nitrogen produced is removed from the reactor via the reflux condenser away. After 2.5 hours at 55 ° C, the gas evolution has ended. The reaction mixture is mixed with 150 ml of methylene chloride and poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated off, the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. After purification of the crude product by distillation, 36.4 g (87.8% of theory) of 2,5-dichloro-3-fluoropyridine are obtained.

Beispiel H8: 2,5-Dichlor-3-fluorpyridinExample H8: 2,5-dichloro-3-fluoropyridine

In einem 500 ml Reaktor aus Polytetrafluoräthylen, der mit Rührwerk, Thermometer und Rückflusskühler ausgerüstet ist, werden 120 g Fluorwasserstoff vorgelegt. Bei einer Temperatur zwischen 0°C und +10°C werden 40,7 g (0,25 mol) 3-Amino-2,5-dichlorpyridin gelöst in 60 ml Dimethylsulfoxid zugetropft. Bei einer Temperatur von +50°C bis 60°C werden in diese Lösung 24,7 g (0,325 mol) Distickstofftrioxid innert 1.5 Stunden eingeleitet. Der entstehende Stickstoff wird über den Rückflusskühler aus dem Reaktor entfernt. Nach insgesamt 3 Stunden bei 50°C bis 60°C ist die Gasentwicklung beendet. Das Reaktionsgemisch wird mit 150 ml Methylenchldorid versetzt und in Eiswasser gegossen. Das zweiphasige Gemisch wird mit konzentrierter Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt, die wässrige Phase mehrmals mit Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet. Nach destillativer Trennung der Lösung erhält man 38,2 g (92,1 % d.Th.) 2,5-Dichlor-3-fluorpyridin.120 g of hydrogen fluoride are placed in a 500 ml reactor made of polytetrafluoroethylene, which is equipped with a stirrer, thermometer and reflux condenser. 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine dissolved in 60 ml of dimethyl sulfoxide are added dropwise at a temperature between 0 ° C. and + 10 ° C. At a temperature of + 50 ° C to 60 ° C, 24.7 g (0.325 mol) of nitrous oxide are introduced into this solution within 1.5 hours. The nitrogen produced is removed from the reactor via the reflux condenser. After a total of 3 hours at 50 ° C to 60 ° C, the gas evolution has ended. The reaction mixture is mixed with 150 ml of methylene chloride and poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated off, the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate. After separation of the solution by distillation, 38.2 g (92.1% of theory) of 2,5-dichloro-3-fluoropyridine are obtained.

Beispiel H9: 5-Chlor-2,3-difluorpyridinExample H9: 5-chloro-2,3-difluoropyridine

In einem 500 ml Reaktor aus Polytetrafluoräthylen, der mit Rührwerk, Thermometer und Rückflusskühler ausgerüstet ist, werden 120 g Fluorwasserstoff vorgelegt. Bei einer Temperatur zwischen 0°C und +10°C werden 40,7 g (0,25 mol) 3-Amino-2,5-dichlorpyridin gelöst in 100 ml Sulfolan zugetropft. Bei einer Temperatur von +50°C werden in diese Lösung 20,7 g (0,3 mol) Natriumnitrit eingetragen. Der entstehende Stickstoff wird über den Rückflusskühler aus dem Reaktor entfernt. Nach 2 Stunden bei +50°C ist die Gasentwicklung beendet. Das Reaktionsgemisch wird mit 150 ml Methylenchlorid versetzt und auf Eiswasser gegossen. Das zweiphasige Gemisch wird mit Ammoniaklösung neutralisiert. Die organische Phase wird abgetrennt und über Natriumsulfat getrocknet. Das Lösungsmittel wird abdestilliert und das Sulfolan/Produktgemisch wird mit 200 ml Sulfolan, 166 g (2,879 mol) Kaliumfluorid und 2 g Tetrabutylammoniumbromid versetzt. Dieses Reaktionsgemisch wird für 7 Stunden bei 179°C gerührt. Anschliessend wird das Produkt direkt aus der Sulfolan-Lösung abdestilliert. Nach destillativer Reinigung des Rohprodukts erhält man das 5-Chlor-2,3- difluorpyridin, Sdp. 137-139°C.120 g of hydrogen fluoride are placed in a 500 ml reactor made of polytetrafluoroethylene, which is equipped with a stirrer, thermometer and reflux condenser. 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine dissolved in 100 ml of sulfolane are added dropwise at a temperature between 0 ° C. and + 10 ° C. 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at a temperature of + 50 ° C. The Any nitrogen that is formed is removed from the reactor via the reflux condenser. After 2 hours at + 50 ° C the gas evolution has ended. The reaction mixture is mixed with 150 ml of methylene chloride and poured onto ice water. The two-phase mixture is neutralized with ammonia solution. The organic phase is separated off and dried over sodium sulfate. The solvent is distilled off and 200 ml of sulfolane, 166 g (2.879 mol) of potassium fluoride and 2 g of tetrabutylammonium bromide are added to the sulfolane / product mixture. This reaction mixture is stirred at 179 ° C. for 7 hours. The product is then distilled off directly from the sulfolane solution. After purification of the crude product by distillation, 5-chloro-2,3-difluoropyridine, b.p. 137-139 ° C. is obtained.

Beispiel H10: 3-Amino-5-chlor-2-fluor-pyridinExample H10: 3-amino-5-chloro-2-fluoropyridine

7.5 g (0.042 mol) 5-Chlor-2-fluor-3-nitro-pyridin werden in 80 ml Ethanol gelöst und in Gegenwart von 1 g Raney-Nickel-Katalysator unter Normaldruck bei einer Temperatur zwischen 20° und 25°C mit Wasserstoff hydriert. Nach einer Hydrierdauer von 20 Stunden wird der Katalysator abgetrennt und das Lösungsmittel abgedampft. Der Rückstand wird in Ethylacetat aufgenommen, durch eine Kieselgel-Schicht filtriert, das Lösungsmittel abgedampft und der Rückstand in Hexan verrieben Anschliessend wird der Niederschlag filtriert und getrocknet. Man erhält so 4,7 g (76%) 3-Amino-5-chlor-2-fluor-pyridin, Smp. 74°C.7.5 g (0.042 mol) of 5-chloro-2-fluoro-3-nitro-pyridine are dissolved in 80 ml of ethanol and in the presence of 1 g of Raney nickel catalyst under normal pressure at a temperature between 20 ° and 25 ° C with hydrogen hydrated. After a hydrogenation period of 20 hours, the catalyst is separated off and the solvent is evaporated off. The residue is taken up in ethyl acetate, filtered through a layer of silica gel, the solvent is evaporated off and the residue is triturated in hexane. The precipitate is then filtered and dried. This gives 4.7 g (76%) of 3-amino-5-chloro-2-fluoropyridine, mp. 74 ° C.

In analoger Weise erhält man die in den anschliessenden Tabellen aufgelisteten Zwischenprodukte der Formeln II und III des erfindungsgemässen Verfahrens.

Figure imgb0008
Figure imgb0009
 The intermediates of the formulas II and III of the process according to the invention listed in the tables below are obtained in an analogous manner.
Figure imgb0008
Figure imgb0009

Claims (30)

1. Verfahren zur Herstellung von 2,3-Difluorpyridinen der Formel I
Figure imgb0010
worin X für Halogen oder Trifluormethyl steht, dadurch gekennzeichnet, dass man ein 3-Amino-2-halogenpyridin der Formel II
Figure imgb0011
worin X die unter Formel I gegebene Bedeutung hat und Y für Brom. Chlor oder Fluor steht, durch Diazotieren in Gegenwart von Fluorwasserstoff in ein 3-Fluor-2-halogenpyridin der Formel III
Figure imgb0012
worin X und Y die unter Formel II gegebene Bedeutung haben, überführt, und erhaltene 3-Fluor-2-halogenpyridine der Formel III, in welchen Y Brom oder Chlor bedeutet, mit einem Fluorierungsmittel behandelt.1. Process for the preparation of 2,3-difluoropyridines of the formula I.
Figure imgb0010
 wherein X is halogen or trifluoromethyl, characterized in that a 3-amino-2-halogenopyridine of the formula II
Figure imgb0011
 wherein X has the meaning given under formula I and Y for bromine. Chlorine or fluorine is by diazotization in the presence of hydrogen fluoride in a 3-fluoro-2-halopyridine of the formula III
Figure imgb0012
 wherein X and Y have the meaning given under formula II, converted, and obtained 3-fluoro-2-halopyridines of the formula III, in which Y is bromine or chlorine, treated with a fluorinating agent. 2. Verfahren zur Herstellung von 2,3-Difluorpyridinen der Formel I
Figure imgb0013
 worin X für Halogen oder Trifluormethyl steht, dadurch gekennzeichnet, dass man ein 3-Amino-2-halogenpyridin der Formel II
Figure imgb0014
worin X die unter Formel I gegebene Bedeutung hat und Y für Brom oder Chlor steht, in Gegenwart von Fluorwasserstoff diazotiert und das entstandene 3-Fluor-2-halogenpyridin der Formel III
Figure imgb0015
worin X und Y die unter Formel II gegebene Bedeutung haben, mit einem Fluorierungsmittel behandelt.2. Process for the preparation of 2,3-difluoropyridines of the formula I.
Figure imgb0013
 wherein X is halogen or trifluoromethyl, characterized in that a 3-amino-2-halogenopyridine of the formula II
Figure imgb0014
 where X has the meaning given under formula I and Y represents bromine or chlorine, diazotized in the presence of hydrogen fluoride and the resulting 3-fluoro-2-halopyridine of the formula III
Figure imgb0015
 wherein X and Y have the meaning given under formula II, treated with a fluorinating agent. 3. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass X für Chlor und Trifluormethyl steht.3. The method according to claim 1 or 2, characterized in that X represents chlorine and trifluoromethyl. 4. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass Y für Fluor oder Chlor steht.4. The method according to claim 1, characterized in that Y represents fluorine or chlorine. 5. Verfahren gemäss Anspruch 2, dadurch gekennzeichnet, dass Y für Chlor steht.5. The method according to claim 2, characterized in that Y represents chlorine. 6. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass X für Chlor oder Trifluormethyl und Y für Chlor oder Fluor stehen.6. The method according to claim 1, characterized in that X is chlorine or trifluoromethyl and Y is chlorine or fluorine. 7. Verfahren gemäss Anspruch 2, dadurch gekennzeichnet, dass X für Chlor oder Trifluormethyl und Y für Chlor steht.7. The method according to claim 2, characterized in that X is chlorine or trifluoromethyl and Y is chlorine. 8. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man als Fluorierungsmittel Kaliumfluorid verwendet.8. The method according to claim 1 or 2, characterized in that potassium fluoride is used as the fluorinating agent. 9. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man als Fluorierungsmittel Kaliumfluorid in Gegenwart eines Katalysators verwendet.9. The method according to claim 1 or 2, characterized in that potassium fluoride is used as fluorinating agent in the presence of a catalyst. 10. Verfahren gemäss Anspruch 9, dadurch gekennzeichnet, dass man als Katalysator Cäsiumfluorid oder einen Kronenäther oder Gemische davon verwendet.10. The method according to claim 9, characterized in that the catalyst used is cesium fluoride or a crown ether or mixtures thereof. 11. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Diazotierung mit einem Ueberschuss von Fluorwasserstoff ausführt.11. The method according to claim 1 or 2, characterized in that one carries out the diazotization with an excess of hydrogen fluoride. 12. Verfahren gemäss Anspruch 11, dadurch gekennzeichnet, dass man die Diazotierung in einem inerten Lösungsmittel durchführt.12. The method according to claim 11, characterized in that one carries out the diazotization in an inert solvent. 13. Verfahren gemäss Anspruch 11, dadurch gekennzeichnet, dass man die Diazotierung in Fluorwasserstoff in einem Autoklaven bei einer Temperatur zwischen -20°C und +100°C und unter dem sich einstellenden Druck durchführt.13. The method according to claim 11, characterized in that one carries out the diazotization in hydrogen fluoride in an autoclave at a temperature between -20 ° C and + 100 ° C and under the resulting pressure. 14. Verfahren gemäss Anspruch 12, dadurch gekennzeichnet, dass man die Diazotierung und Zersetzung bei einer Temperatur zwischen 0°C und +70°C unter Normaldruck durchführt.14. The method according to claim 12, characterized in that one carries out the diazotization and decomposition at a temperature between 0 ° C and + 70 ° C under normal pressure. 15. Verfahren gemäss Anspruch 13, dadurch gekennzeichnet, dass die Temperatur zwischen -10°C und +70°C liegt.15. The method according to claim 13, characterized in that the temperature is between -10 ° C and + 70 ° C. 16. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man als Diazotierungsmittel Natriumnitrit oder Distickstofftrioxid verwendet.16. The method according to claim 1 or 2, characterized in that sodium nitrite or nitrous oxide is used as the diazotizing agent. 17. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Diazotierung mittels Natriumnitrit oder Distickstofftrioxid in Fluorwasserstoff mit einem inerten Lösungsmittel bei einer Temperatur zwischen 0°C und +70°C unter Normaldruck ausführt.17. The method according to claim 1 or 2, characterized in that one carries out the diazotization by means of sodium nitrite or dinitrogen trioxide in hydrogen fluoride with an inert solvent at a temperature between 0 ° C and + 70 ° C under normal pressure. 18. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Substitution von Chlor oder Brom in 2-Stellung des Pyridinringes durch Fluor in einem polaren aprotischen Lösungsmittel durchführt.18. The method according to claim 1 or 2, characterized in that one carries out the substitution of chlorine or bromine in the 2-position of the pyridine ring by fluorine in a polar aprotic solvent. 19. Verfahren gemäss Anspruch 18, dadurch gekennzeichnet, dass man als Lösungsmittel Dimethylsulfoxid, Dimethylsulfon, Sulfolan, Dimethylacetamid, N-Methylpyrrolidinon oder Dimethylformamid verwendet.19. The method according to claim 18, characterized in that the solvent used is dimethyl sulfoxide, dimethyl sulfone, sulfolane, dimethylacetamide, N-methylpyrrolidinone or dimethylformamide. 20. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Substitution von Chlor oder Brom in 2-Stellung des Pyridinringes durch Fluor bei einer Temperatur zwischen 80°C und 220°C durchführt.20. The method according to claim 1 or 2, characterized in that one carries out the substitution of chlorine or bromine in the 2-position of the pyridine ring by fluorine at a temperature between 80 ° C and 220 ° C. 21. Verfahren gemäss Anspruch 20, dadurch gekennzeichnet, dass die Temperatur zwischen 120°C und 170°C liegt.21. The method according to claim 20, characterized in that the temperature is between 120 ° C and 170 ° C. 22. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Substitution von Chlor oder Brom in 2-Stellung des Pyridinringes durch Fluor unmittelbar nach der Diazotierung des 3-Amino-2- halogenpyridins der Formel II ohne Isolierung des 3-Fluor-2-halogen- pyridins der Formel III bei einer Temperatur zwischen 80°C und 170°C durchführt.22. The method according to claim 1 or 2, characterized in that the substitution of chlorine or bromine in the 2-position of the pyridine ring by fluorine immediately after the diazotization of the 3-amino-2-halogenopyridine of the formula II without isolation of the 3-fluorine 2-halogenopyridine of the formula III at a temperature between 80 ° C and 170 ° C. 23. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man dem Fluorierungsmittel Kaliumfluorid, 0,001 Mol bis 0,1 Mol an Fluorierungskatalysator pro Mol zu fluorierendes Ausgangsmaterial zusetzt.23. The method according to claim 1 or 2, characterized in that the fluorinating agent potassium fluoride, 0.001 mol to 0.1 mol of fluorination catalyst per mol of starting material to be fluorinated is added. 24. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Substitution von Chlor oder Brom in 2-Stellung des Pyridinringes durch Fluor in Dimethylsulfoxid, Sulfolan, Dimethylformamid oder Dimethylacetamid mit Kaliumfluorid in Gegenwart von 0,001 Mol bis 0,1 Mol Cäsiumfluorid pro Mol an Ausgangsmaterial bei einer Temperatur zwischen 120°C und 170°C durchführt.24. The method according to claim 1 or 2, characterized in that the substitution of chlorine or bromine in the 2-position of the pyridine ring by fluorine in dimethyl sulfoxide, sulfolane, dimethylformamide or dimethylacetamide with potassium fluoride in the presence of 0.001 mol to 0.1 mol of cesium fluoride per Mol of starting material at a temperature between 120 ° C and 170 ° C. 25. Verfahren gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass man die Diazotierung mittels Natriumnitrit oder Distickstofftrioxid in Fluorwasserstoff mit einem inerten Lösungsmittel bei einer Temperatur zwischen 0°C und +70°C unter Normaldruck ausführt, und die Substitution von Chlor oder Brom in 2-Stellung des Pyridinringes durch Fluor in Dimethylsulfoxid oder Sulfolan mit Kaliumfluorid in Gegenwart von 0,001 Mol bis 0,1 Mol Cäsiumfluorid pro Mol an Ausgangsmaterial bei einer Temperatur zwischen 120°C und 170°C durchführt.25. The method according to claim 1 or 2, characterized in that one carries out the diazotization by means of sodium nitrite or dinitrogen trioxide in hydrogen fluoride with an inert solvent at a temperature between 0 ° C and + 70 ° C under normal pressure, and the substitution of chlorine or bromine in 2-position of the pyridine ring by fluorine in dimethyl sulfoxide or sulfolane with potassium fluoride in the presence of 0.001 mol to 0.1 mol of cesium fluoride per mol of starting material at a temperature between 120 ° C and 170 ° C. 26. Verbindungen der Formel IIa
Figure imgb0016
worin X für Halogen und Y für Brom, Chlor oder Fluor stehen.26. Compounds of formula IIa
Figure imgb0016
 where X is halogen and Y is bromine, chlorine or fluorine. 27. Verbindungen der Formel IIa gemäss Anspruch 26, worin X für Halogen und Y für Brom oder Chlor stehen.27. Compounds of formula IIa according to claim 26, wherein X is halogen and Y is bromine or chlorine. 28. Verbindungen der Formel IIIa
Figure imgb0017
worin X für Halogen und Y für Brom oder Chlor stehen.28. Compounds of formula IIIa
Figure imgb0017
 where X is halogen and Y is bromine or chlorine. 29. 2,5-Dichlor-3-fluor-pyridin gemäss Anspruch 28.29. 2,5-dichloro-3-fluoropyridine according to claim 28. 30. 3-Amino-5-chlor-2-fluorpyridin gemäss Anspruch 26. FO 7.5/CW/cs* 30. 3-amino-5-chloro-2-fluoropyridine according to claim 26. FO 7.5 / CW / cs *
EP85810455A 1984-10-10 1985-10-04 Process for the preparation of fluorinated pyridine derivatives Expired - Lifetime EP0178260B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85810455T ATE52775T1 (en) 1984-10-10 1985-10-04 PROCESS FOR THE PREPARATION OF FLUORINATED PYRIDINE DERIVATIVES.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH485584 1984-10-10
CH4855/84 1984-10-10

Publications (3)

Publication Number Publication Date
EP0178260A2 true EP0178260A2 (en) 1986-04-16
EP0178260A3 EP0178260A3 (en) 1987-01-07
EP0178260B1 EP0178260B1 (en) 1990-05-16

Family

ID=4283718

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85810455A Expired - Lifetime EP0178260B1 (en) 1984-10-10 1985-10-04 Process for the preparation of fluorinated pyridine derivatives

Country Status (7)

Country Link
US (1) US4831148A (en)
EP (1) EP0178260B1 (en)
JP (2) JPS6191171A (en)
AT (1) ATE52775T1 (en)
CA (1) CA1226865A (en)
DE (1) DE3577704D1 (en)
IL (1) IL76616A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0227047A2 (en) * 1985-12-21 1987-07-01 Hoechst Aktiengesellschaft Pyridine derivatives and their N-oxides, process for their preparation and their use as intermediates
EP0508215A1 (en) * 1991-04-06 1992-10-14 Bayer Ag Process for the preparation of 2-chloro-pyridines
CN106279003A (en) * 2016-07-13 2017-01-04 南京红太阳生物化学有限责任公司 A kind of preparation method of 2 chlorine 5 picolines

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4999432A (en) * 1989-08-28 1991-03-12 Dowelanco Fluorination with hydrogen fluoride
US5027520A (en) * 1990-08-15 1991-07-02 Finnegan Danny E Farrier's instrument
US5274100A (en) * 1990-10-23 1993-12-28 Ciba-Geigy Corporation Process for the preparation of (3-fluoropyridin-2-yloxy)phenoxypropionic acids
CN102532008A (en) * 2012-01-12 2012-07-04 南京红太阳生物化学有限责任公司 Novel method for synthesizing 2,5-dichloro-3-fluoropyridine
US9126905B2 (en) * 2012-07-18 2015-09-08 Basf Se Process for manufacturing fluoroaromatics
CN115108971A (en) * 2022-06-30 2022-09-27 杭州凯氟科技有限公司 Preparation method of 2, 3-difluoro-5-chloropyridine

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3703521A (en) * 1971-03-22 1972-11-21 Olin Corp Method for the preparation of stable 4-fluoropyridine salts
GB1344636A (en) * 1970-10-30 1974-01-23 Ici Ltd Manufacture of halogenated pyridine derivatives
DE2409379A1 (en) * 1974-02-27 1975-09-04 Olin Corp Difluoropyridines prepd from diaminopyridines - by diazotisation in presence of hydrogen fluoride, useful as herbicides
US4031100A (en) * 1976-08-23 1977-06-21 The Dow Chemical Company Process for making 2,6-difluoropyridine
US4071521A (en) * 1976-08-23 1978-01-31 The Dow Chemical Company Process for making 2,6-difluoro pyridine
FR2359106A1 (en) * 1976-07-23 1978-02-17 Olin Corp PROCESS FOR DIAZOTATION-FLUORATION OF AROMATIC OR HETEROCYCLIC AMINES IN A HYDROFLUORIC MEDIUM CONTAINING AMMONIUM IONS
GB2039473A (en) * 1979-01-11 1980-08-13 Dow Chemical Co Reaction of a chlorinated pyridine with an alkali metal fluoride
GB2053189A (en) * 1979-07-12 1981-02-04 Pfizer Ltd Antifungal pyridine-2-thiones
EP0097460A1 (en) * 1982-06-18 1984-01-04 The Dow Chemical Company Pyridyl(oxy/thio)phenoxy compounds, herbicidal compositions and methods
DE3234451A1 (en) * 1982-09-17 1984-03-22 Hoechst Ag, 6230 Frankfurt Novel pyridylureas, process for their preparation, agents containing them, and their use as herbicides

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2563796A (en) * 1948-05-26 1951-08-07 Harshaw Chem Corp Manufacture of aromatic diazonium fluorides and corresponding aromatic fluorides
JPS5314057B2 (en) * 1972-12-15 1978-05-15
GB1415825A (en) * 1974-02-26 1975-11-26 Olin Corp Method for the preparation of difluoropyridines
US4096196A (en) * 1975-10-31 1978-06-20 Olin Corporation Diazotization-fluorination in a medium of hydrogen fluoride containing tertiary amine compounds
JPS5368783A (en) * 1976-12-01 1978-06-19 Ishihara Sangyo Kaisha Ltd Preparation of 2,3,5-trichloropyridine
US4505743A (en) * 1981-12-31 1985-03-19 Ciba-Geigy Corporation α-[4-(3-Fluoro-5'-halopyridyl-2'-oxy)-phenoxy]-propionic acid derivatives having herbicidal activity
JPS58219163A (en) * 1982-06-16 1983-12-20 Dainippon Ink & Chem Inc Preparation of fluoroheterocyclic compound
JPS59283A (en) * 1982-06-25 1984-01-05 Hitachi Ltd Skew distortion correcting circuit
US4480102A (en) * 1982-07-23 1984-10-30 The Dow Chemical Company 2,3-Difluoro-5-(trifluoromethyl)pyridine and methods of making and using the same

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1344636A (en) * 1970-10-30 1974-01-23 Ici Ltd Manufacture of halogenated pyridine derivatives
US3703521A (en) * 1971-03-22 1972-11-21 Olin Corp Method for the preparation of stable 4-fluoropyridine salts
DE2409379A1 (en) * 1974-02-27 1975-09-04 Olin Corp Difluoropyridines prepd from diaminopyridines - by diazotisation in presence of hydrogen fluoride, useful as herbicides
FR2359106A1 (en) * 1976-07-23 1978-02-17 Olin Corp PROCESS FOR DIAZOTATION-FLUORATION OF AROMATIC OR HETEROCYCLIC AMINES IN A HYDROFLUORIC MEDIUM CONTAINING AMMONIUM IONS
US4031100A (en) * 1976-08-23 1977-06-21 The Dow Chemical Company Process for making 2,6-difluoropyridine
US4071521A (en) * 1976-08-23 1978-01-31 The Dow Chemical Company Process for making 2,6-difluoro pyridine
GB2039473A (en) * 1979-01-11 1980-08-13 Dow Chemical Co Reaction of a chlorinated pyridine with an alkali metal fluoride
GB2053189A (en) * 1979-07-12 1981-02-04 Pfizer Ltd Antifungal pyridine-2-thiones
EP0097460A1 (en) * 1982-06-18 1984-01-04 The Dow Chemical Company Pyridyl(oxy/thio)phenoxy compounds, herbicidal compositions and methods
DE3234451A1 (en) * 1982-09-17 1984-03-22 Hoechst Ag, 6230 Frankfurt Novel pyridylureas, process for their preparation, agents containing them, and their use as herbicides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Berrie et al, J. Chem. Soc. 1952 2042 *
J. Fluor. Chem. 1982, 171-89 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0227047A2 (en) * 1985-12-21 1987-07-01 Hoechst Aktiengesellschaft Pyridine derivatives and their N-oxides, process for their preparation and their use as intermediates
EP0227047A3 (en) * 1985-12-21 1988-09-21 Hoechst Aktiengesellschaft Pyridine derivatives and their n-oxides, process for their preparation and their use as intermediates
EP0508215A1 (en) * 1991-04-06 1992-10-14 Bayer Ag Process for the preparation of 2-chloro-pyridines
US5283338A (en) * 1991-04-06 1994-02-01 Bayer Aktiengesellschaft Process for the preparation of 2-chloropyridines
CN106279003A (en) * 2016-07-13 2017-01-04 南京红太阳生物化学有限责任公司 A kind of preparation method of 2 chlorine 5 picolines

Also Published As

Publication number Publication date
EP0178260B1 (en) 1990-05-16
CA1226865A (en) 1987-09-15
IL76616A (en) 1989-06-30
DE3577704D1 (en) 1990-06-21
ATE52775T1 (en) 1990-06-15
JPH07165718A (en) 1995-06-27
EP0178260A3 (en) 1987-01-07
JP2500229B2 (en) 1996-05-29
JPS6191171A (en) 1986-05-09
US4831148A (en) 1989-05-16
IL76616A0 (en) 1986-02-28

Similar Documents

Publication Publication Date Title
DE3008908C2 (en)
DE3010195C2 (en)
EP0178260B1 (en) Process for the preparation of fluorinated pyridine derivatives
DE102004033525A1 (en) Improved process for the production of ring-fluorinated aromatics
EP0373464A2 (en) Process for the preparation of 2-chloro-5-chloromethyl pyridine
EP0072777A2 (en) Process for the preparation of 2-chloropyridines
EP0132733A2 (en) Fluoropivalic-acid fluorides and process for producing them
EP0244359B1 (en) Process for the preparation of pyrimidine derivatives
EP0003562B1 (en) Process for the preparation of hydroxyphenyl ethers
EP0439745B1 (en) Process for the preparation of 2-chloro-5-methyl-pyridine
EP0569947A1 (en) Process for the production of 2-chloro-5-chloromethyl-pyridine
DE69926223T2 (en) PROCESS FOR PRODUCING INTERMEDIATE PRODUCTS
EP0187285A2 (en) Process for the preparation of substituted phenyl hydrazines
EP0115811B1 (en) 2,4-dichlor-5-thiazolecarboxaldehyd and a process for its preparation
DE1078582B (en) Process for the production of substituted thyropropionic acids
EP0157225B1 (en) Process for the production of benzimidazolyl, benzoxazolyl and benzothiazolyl oxyphenoxypropionate derivatives
EP0302227B1 (en) 5-halo-6-amino-nicotinic acid halides, their preparation and their use
DE3529259A1 (en) Process for the preparation of halogen-substituted benzoylacetonitriles, 1-chloro-2(2,4-dichloro-5-fluorophenyl)ethane-2-one and its preparation
CH409903A (en) Process for the production of organic fluorine compounds
EP0090769B1 (en) Process for the preparation of 1,2,5,6-tetrahydro-4h-pyrrolo(3,2,1-ij)-quinolin-4-one and 5-halo-1,2,3-(1,2,dihydropyrrolo)-4-quinolone intermediates
EP0483061B1 (en) Process for the preparation of 4-(3-fluoro-pyridine-2-yloxy)-phenoxy-propionic acids
EP0290903B1 (en) Beta-fluoracyl-beta-halogen vinyl alkyl ethers
DE4208778C1 (en)
EP0074488B1 (en) 2-azido-3-benzyloxy-propionic-acid benzyl ester, process for its preparation and its use
EP0662474B1 (en) Process for the preparation of chloropyridines

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19851007

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE FR GB IT LI NL

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE FR GB IT LI NL

17Q First examination report despatched

Effective date: 19880811

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI NL

REF Corresponds to:

Ref document number: 52775

Country of ref document: AT

Date of ref document: 19900615

Kind code of ref document: T

ITF It: translation for a ep patent filed

Owner name: BARZANO' E ZANARDO MILANO S.P.A.

REF Corresponds to:

Ref document number: 3577704

Country of ref document: DE

Date of ref document: 19900621

ET Fr: translation filed
GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
ITTA It: last paid annual fee
REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Free format text: CIBA-GEIGY AG TRANSFER- NOVARTIS AG

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

NLS Nl: assignments of ep-patents

Owner name: NOVARTIS AG

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: SYNGENTA PARTICIPATIONS AG

Free format text: NOVARTIS AG#SCHWARZWALDALLEE 215#4058 BASEL (CH) -TRANSFER TO- SYNGENTA PARTICIPATIONS AG#SCHWARZWALDALLEE 215#4058 BASEL (CH)

NLS Nl: assignments of ep-patents

Owner name: SYNGENTA PARTICIPATIONS AG

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20040929

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20040930

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20041003

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20041008

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20041013

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20041015

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20041217

Year of fee payment: 20

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20051003

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20051004

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

BE20 Be: patent expired

Owner name: *SYNGENTA PARTICIPATIONS A.G.

Effective date: 20051004

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

NLV7 Nl: ceased due to reaching the maximum lifetime of a patent

Effective date: 20051004

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

BE20 Be: patent expired

Owner name: *SYNGENTA PARTICIPATIONS A.G.

Effective date: 20051004